DNMT1 recruited by EZH2-mediated silencing of miR-484 contributes to the malignancy of cervical cancer cells through MMP14 and HNF1A

Emerging evidence indicates that dysregulation of microRNAs (miRNAs) contributes to cervical cancer (CC) tumorigenesis and development. Previous work showed that miR-484 which regulated the EMT process was obviously downregulated in CC. However, little is known about the precise mechanism. We found that the deficiency of EZH2-recruited DNA methyltransferases DNMT1 reduced the CpG methylation of miR-484 promoter and then increased the miR-484 expression. Furthermore, the cell membrane-bound matrix metalloproteinase (MMP14) and the hepatocyte nuclear factor 1A (HNF1A) were found to be downregulated by miR-484. miR-484 repressed the expression of MMP14 and HNF1A inhibiting CC growth and metastasis in vitro and in vivo. Upregulation of MMP14 and HNF1A promotes the CC cell adhesion and EMT, all of which contribute to cell motility and metastasis. Moreover, miR-484 negatively regulates the WNT/MAPK and TNF signaling pathway by downregulating HNF1A and MMP14 respectively. Thus, miR-484, who is downregulated by DNMT1-mediated hypermethylation in its promoter, functions as a tumor suppressor by inhibiting MMP14 and HNF1A expression in CC. Our finding characterizes miR-484 as a key suppressive regulator in CC metastasis and reveals a DNMT1-mediated epigenetic mechanism for miR-484 silencing, expanding our understanding of the molecular mechanism underlying CC progression and metastasis.